The association of donor age and survival is independent of ischemic time following deceased donor lung transplantation

Mulvihill, Michael S.; Gulack, Brian C.; Ganapathi, Asvin M.; Speicher, Paul J.; Englum, Brian R.; Hirji, Sameer; Snyder, Laurie D.; Davis, R. Benjamin; Hartwig, Matthew G.

doi:10.1111/ctr.12993

Cited by 23 publications

(13 citation statements)

References 19 publications

(28 reference statements)

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“…Controlling innate immunity early on post-transplantation is a key component of innovative strategies to promote allograft acceptance 2 , 3 . Furthermore, critical organ shortages have necessitated the increased use of organs from donors of older age or with co-morbid diseases for transplantation 4 – 6 . Owing to pre-existing damage, these organs have shorter expected duration of function and more readily accumulate ischemic injuries, which can further compromise their long-term outcomes 7 – 13 .…”

Section: Introductionmentioning

confidence: 99%

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

Uehara

Solhjou

Banouni

et al. 2018

Sci Rep

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Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.

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Section: Introductionmentioning

confidence: 99%

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

Uehara

Solhjou

Banouni

et al. 2018

Sci Rep

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“…In terms of attribute “exchange rates,” 25 LAS points equates to just 143 NM, implying that a nearby candidate with LAS of 45 would be prioritized ahead of a LAS 70 candidate just 150 NM further away. The rationale for prioritizing patients based on proximity reflects both system efficiency and organ viability considerations, as transporting lungs over long distances incurs transportation costs, travel time by the surgical recovery team, and potentially detrimental effects of organ ischemia time [ 15 – 19 ]. The manner and degree to which proximity should influence candidate rankings is a matter of ongoing debate [ 20 – 22 ].…”

Section: Discussionmentioning

confidence: 99%

A revealed preference analysis to develop composite scores approximating lung allocation policy in the U.S

Stewart¹,

Wood

Alcorn³

et al. 2021

BMC Med Inform Decis Mak

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Background The patient ranking process for donor lung allocation in the United States is carried out by a classification-based, computerized algorithm, known as the match system. Experts have suggested that a continuous, points-based allocation framework would better serve waiting list candidates by removing hard boundaries and increasing transparency into the relative importance of factors used to prioritize candidates. We applied discrete choice modeling to match run data to determine the feasibility of approximating current lung allocation policy by one or more composite scores. Our study aimed to demystify the points-based approach to organ allocation policy; quantify the relative importance of factors used in current policy; and provide a viable policy option that adapts the current, classification-based system to the continuous allocation framework. Methods Rank ordered logistic regression models were estimated using 6466 match runs for 5913 adult donors and 534 match runs for 488 pediatric donors from 2018. Four primary attributes are used to rank candidates and were included in the models: (1) medical priority, (2) candidate age, (3) candidate’s transplant center proximity to the donor hospital, and (4) blood type compatibility with the donor. Results Two composite scores were developed, one for adult and one for pediatric donor allocation. Candidate rankings based on the composite scores were highly correlated with current policy rankings (Kendall’s Tau ~ 0.80, Spearman correlation > 90%), indicating both scores strongly reflect current policy. In both models, candidates are ranked higher if they have higher medical priority, are registered at a transplant center closer to the donor hospital, or have an identical blood type to the donor. Proximity was the most important attribute. Under a points-based scoring system, candidates in further away zones are sometimes ranked higher than more proximal candidates compared to current policy. Conclusions Revealed preference analysis of lung allocation match runs produced composite scores that capture the essence of current policy while removing rigid boundaries of the current classification-based system. A carefully crafted, continuous version of lung allocation policy has the potential to make better use of the limited supply of donor lungs in a manner consistent with the priorities of the transplant community.

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“…In terms of attribute "exchange rates," 25 LAS points equates to just 143 NM, implying that a nearby candidate with LAS of 45 would be prioritized ahead of a LAS 70 candidate just 150 NM further away. The rationale for prioritizing patients based on proximity re ects both system e ciency and organ viability considerations, as transporting lungs over long distances incurs transportation costs, travel time by the surgical recovery team, and potentially detrimental effects of organ ischemia time [15][16][17][18][19]. The manner and degree to which proximity should in uence candidate rankings is a matter of ongoing debate [20][21][22].…”

Section: Discussionmentioning

confidence: 99%

A Revealed Preference Analysis to Develop Composite Scores Approximating Lung Allocation Policy in the U.S.

Stewart¹,

Wood

Alcorn³

et al. 2020

Preprint

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Background: The patient ranking process for donor lung allocation in the United States is carried out by a classification-based, computerized algorithm, known as the match system. Experts have wondered whether a continuous, points-based allocation framework would better serve waiting list candidates by removing hard boundaries and increasing transparency into the relative importance of factors used to order candidates. We applied discrete choice modeling to match run data to determine the feasibility of approximating current lung allocation policy by one or more composite scores. Our study aimed to demystify the points-based approach to allocation; quantify the relative importance of factors used in allocation under current policy; and provide a viable policy option that adapts the current, classification-based system to the continuous allocation framework.Methods: Rank ordered logistic regression models were estimated using 6,466 match runs for 5,913 adult donors and 534 match runs for 488 pediatric donors from 2018. Four primary attributes are used to rank candidates and were included in the models: (1) medical priority, (2) candidate age, (3) candidate’s transplant center proximity to the donor hospital, and (4) blood type compatibility with the donor.Results: Two composite scores were developed, one for adult and one for pediatric donor allocation. Candidate rankings based on the composite scores were highly correlated with current policy rankings (Kendall’s Tau ~0.80, Spearman correlation >90%), indicating both scores strongly reflect current policy. In both models, candidates are ranked higher if they have higher medical priority, are registered at a transplant center closer to the donor hospital, or have an identical blood type to the donor. Proximity was the most important attribute. Under a points-based scoring system, candidates in further away zones are sometimes ranked higher than more proximal candidates compared to current policy. Conclusions: Revealed preference analysis of match runs produced composite scores that capture the essence of current policy while removing hard boundaries of the current classification-based system. A carefully crafted, continuous version of lung allocation policy has the potential to make better use of the limited supply of donor lungs in a manner consistent with the priorities of the transplant community.

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The association of donor age and survival is independent of ischemic time following deceased donor lung transplantation

Cited by 23 publications

References 19 publications

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

A revealed preference analysis to develop composite scores approximating lung allocation policy in the U.S

A Revealed Preference Analysis to Develop Composite Scores Approximating Lung Allocation Policy in the U.S.

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